tert-butyl 3-aminobenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.19 g (0.38 mmol) of [1-(isopropyl-phenyl-carbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]acetic acid, prepared as in Intermediate 7, 0.15 g (0.76 mmol) of t-butyl 3-aminobenzoate, 0.35 g (0.76 mmol) of PyBrOP and 0.27 mL (1.5 mmol) of N,N-diisopropyl-N-ethylamine in 2 mL of DMF is stirred at 50° C. for 17 h. The reaction mixture is diluted with 30 mL of H2O and extracted with EtOAc (×3). The organic extract is washed with H2O, 1N HCl, and brine, dried over MgSO4 and concentrated in vacuo to a brown foam. The crude product is dissolved in 2 mL of CH2Cl2 and 0.3 mL (3.8 mmol) of TFA added. After stirring at RT for 1 d, the reaction mixture is concentrated in vacuo to a brown oil. Purification by reverse phase C-18 MPLC (60-80% methanol/TFA-H2O) gave 99 mg of the title compound as a white powder: 1H NMR (CDCl3 300 MHz, mixture of conformations) δ8.8-6.8 (m, 20H), 5.07 (m, 1H), 4.78 (d, 1H, J=12), 3.79 (d, 1H, J=12), 2.70 (q, 2H, J=10), 1.70 (s, 3H), 1.09 (m, 6H); low resolution MS (FAB) m/e 619 (MH+); Anal. (C36H34N4O6.0.75 TFA.H2O) Calc. C, 62.4; H, 5.1; N, 7.8; Found: C, 62.4; H, 5.2; N, 7.7. extracted with EtOAc (×3) The organic extract is washed with H2O, 1N HCl, and brine dried over MgSO4 concentrated in vacuo to a brown foam The crude product is dissolved in 2 mL of CH2Cl2 After stirring at RT for 1 d the reaction mixture is concentrated in vacuo to a brown oil Purification by reverse phase C-18 MPLC (60-80% methanol/TFA-H2O)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-nitrophenylacetic acid (5 g), benzyl alcohol (2.9 ml) and 4,4-dimethylaminopyridine (300 mg) in dry dichloromethane (50 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7.4 g). The resulting yellow mixture was stirred at 23° for 3 days whereupon the solvent was removed in vacuo. The residue was partitioned between water (100 ml) and ethyl actate (100 ml) and the organic phase washed with water (2×100 ml) and saturated brine (100 ml) then dried and evaporated. The residue was chromatographed with hexane-EA (4:1) as eluent then again with isohexane-DCM (1:1) as eluent to give the title compound (2.05 g) as a pale yellow oil. was removed in vacuo The residue was partitioned between water (100 ml) and ethyl actate (100 ml) the organic phase washed with water (2×100 ml) and saturated brine (100 ml) then dried evaporated The residue was chromatographed with hexane-EA (4:1) as eluent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-nitrophenylacetic acid (5 g), benzyl alcohol (2.9 ml) and 4,4-dimethylaminopyridine (300 mg) in dry dichloromethane (50 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7.4 g). The resulting yellow mixture was stirred at 23° for 3 days whereupon the solvent was removed in vacuo. The residue was partitioned between water (100 ml) and ethyl actate (100 ml) and the organic phase washed with water (2×100 ml) and saturated brine (100 ml) then dried and evaporated. The residue was chromatographed with hexane-EA (4:1) as eluent then again with isohexane-DCM (1:1) as eluent to give the title compound (2.05 g) as a pale yellow oil. was removed in vacuo The residue was partitioned between water (100 ml) and ethyl actate (100 ml) the organic phase washed with water (2×100 ml) and saturated brine (100 ml) then dried evaporated The residue was chromatographed with hexane-EA (4:1) as eluent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 3-(N-benzyloxycarbonylamino)benzoate (2.18 g) and ammonium formate (2.1 g) were dissolved in methanol (30 ml). Catalyst (1 g) of 10% palladium/carbon was added, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was filtered through Celite to remove catalyst and the filtrate was concentrated. The residue was partitioned between chloroform and water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 3-aminobenzoate. This compound was dissolved in tetrahydrofuran (30 ml). N,N'-Carbonyldiimidazole (1.05 g) was added, and the mixture was stirred at room temperature for 3 hours. Triethylamine (1.82 ml) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (4.82 g) were added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol (10:1) as an eluent, and crystallized from isopropyl ether to give 0.95 g of tert-butyl 3-(3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)ureido)benzoate. The reaction mixture was filtered through Celite to remove catalyst the filtrate was concentrated The residue was partitioned between chloroform and water The organic layer was washed with water dried over magnesium sulfate concentrated under reduced pressure